Naltrexone is a well-known opioid receptor antagonist with no opioid agonist properties. Low doses of naltrexone have been investigated in patients with multiple sclerosis, autism, active Crohn's disease, AIDS, rheumatoid arthritis, celiac disease, certain forms of cancer, and autoimmune diseases. Opioids act as cytokines, the principal communication signalers of the immune system, creating immunomodulatory effects through opioid receptors on immune cells. Very low doses of naltrexone, of approximately one-tenth the usual dosage, boosts the immune system and helps to fight against diseases characterized by inadequate immune function. However naltrexone is used most commonly in the treatment of alcohol dependence (alcoholism) and opiate addiction.
In terms of pharmacology, naltrexone blocks the effects of opioids by its highly competitive binding at the μ-opioid receptors. Being a competitive antagonist, the suppression of an opiate's agonistic, euphorigenic effect can be overcome. However, clinical studies have indicated that naltrexone in an oral dosage of approximately 50 mg is able to block the pharmacological effects of up to 25 mg of intravenously administered heroin for periods as long as twenty four hours.
The mechanism of action of naltrexone in the treatment of alcoholism is not understood although involvement of the endogenous opioid system is suggested by pre-clinical data. Opioid antagonists have been shown to reduce alcohol consumption by animals, and naltrexone has shown efficacy in maintaining abstinence in clinical studies in humans.
Although well absorbed orally (approximately 96% of an oral dose is absorbed from the gastrointestinal tract), naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5% to 40%.
The activity of naltrexone is believed to be as a result of both naltrexone and its 6-β-naltrexol metabolite. Two other minor metabolites are 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methyl-naltrexone. Peak plasma levels of both naltrexone and 6-β-naltexol occur within one hour after oral dosing; mean elimination half-life values for naltrexone and 6-β-naltrexol are four and thirteen hours respectively.
In terms of its use in the clinic, naltrexone tablets, as an adjunctive treatment of alcoholism, are typically used in a dosing regimen of 50 mg once daily for up to 12 weeks. A flexible approach to a dosing regimen tends to be employed to enhance patient compliance. Thus, patients may receive 50 mg of oral naltrexone every weekday, with a 100 mg dose on Saturday, or patients may receive 100 mg every other day, or 150 mg every third day. The systemic daily dose may vary between 2.5 and 20 mg, taking into account the oral dose and the bioavailability of naltrexone.
Whilst the oral administration of any drug has clear advantages, issues of patient non-compliance are particular concerns with the use of naltrexone in the treatment of alcoholism and for the treatment of opiate addiction. For example, naltrexone is a major liver toxin, which precludes oral administration in a significant number of alcoholics. Its long half-life also has the effect that there are significant quantities of it in the body after a period during the day when an alcoholic undergoing treatment may be permitted to drink. Clinicians generally prefer that a low build-up of an antagonist in the body before a session and its continued presence after the session should be avoided as much as possible. Accordingly, whilst naltrexone is the first new anti-alcoholism drug to receive approval from the Food and Drug Administration in the United States in many years, patient non-compliance, coupled with adverse gastro-intestinal effects, and variation in metabolic effects between even complying patients, limit the clinical usefulness of naltrexone.
As an alternative to oral administration, the use of depot injections of naltrexone have been investigated but such a way of administering of naltrexone is undesirable. For example, such depot injections are highly invasive and have additional pharmacological problems associated with inconsistent initial and sustained rates of delivery, inadequate release rates and site-of injection reactions. Nevertheless, injectable naltrexone is indicated or the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment. The recommended dose of 380 mg is administered intramuscularly every 4 weeks (once a month). This equates to an average daily dose is 12.5 mg with such a formulation.
In the treatment of opiate dependence, a dose of 50 mg once a day produces adequate clinical blockade of the actions of parenterally administered opiates. As with many non-agonist treatments for addiction, oral naltrexone is of proven value only when given as part of a comprehensive treatment plan that includes measures to ensure the patient compliance.
Naltrexone has very few and minor side effects, and may be the treatment of choice in highly motivated patients. However, clinical experience using oral naltrexone for treating opiate dependence has been replete with data of poor medication compliance according to several reports.
In conclusion, whilst naltrexone is available as once-a-day 50 mg oral tablets for the treatment of alcohol dependence and for opiate addiction, and as once-a-month injections for the treatment of alcohol dependence. There is a need to develop alternative non-invasive, controlled-released dosage formulations and methods of delivery for naltrexone as a consequence of the disadvantages reported above in relation to existing modes of naltrexone delivery using oral and injection-based deliveries.
Transdermal administration of drugs is often advantageous: it eliminates first-pass metabolism, and reduces gastro intestinal side-effects, and the invasiveness of the intramuscular depot injections known in the art. However, naltrexone does not present itself as an optimum or obvious candidate for transdermal delivery. This is, in part, as a consequence of the relatively high dosages required (for example between 2.5 mg and 20 mg per day) and because of a difficulty in achieving permeation through the skin, amongst other drugs. In EP-A-178140 (Alza Corporation) it is reported that the low permeability of naltrexone through the skin led to unsuccessful attempts to increase its permeation by the contemporaneous administration of conventional permeation enhancers. It is reported in that patent publication that the base form of naltrexone could be delivered through intact skin at fluxes capable of producing therapeutic effects if delivered in the presence of permeation-enhancing amounts of polyethylene-glycol monolaurate although this not in fact exemplified in the published application in respect of naltrexone.
Since the mid 1980s, when EP-A-178140 was published, there have been a large number of reports in relation to the search for a formulation capable of allowing effective transdermal delivery of naltrexone. Commonly, as an alternative to seeking delivery of the base form of naltrexone, efforts have focused on the development of lipophilic prodrugs of naltrexone for transdermal administration (for example naltrexone-3-(2′ethylbutyrate), naltrexone-3-valerate, naltrexone-ethyl butyryl ester and naltrexone dimethyl carbamate). Such prodrugs are hydrolyzed to naltrexone upon passing through the skin. For an example of a report regarding naltrexone prodrugs see S. Valiveti et al, (J. Control. Release 102, 509-520 (2005)).